Medical Devices, Wound Dressings, and Methods for Dressing Wounds

ABSTRACT

Medical devices, wound dressings, and methods of dressing wounds are described. Devices and methods using silicone and pharmaceutically active agents are described. Devices including covers and bases are described.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/414,598 which was filed on Nov. 17, 2010; U.S. Provisional PatentApplication No. 61/449,038 which was filed on Mar. 3, 2011; U.S. patentapplication Ser. No. 12/690,081 which was filed on Mar. 22, 2010, whichis a continuation in part of, and claims priority to, U.S. patentapplication Ser. No. 12/162,990 filed Jul. 31, 2008, claiming priorityto International Patent Application No. PCT/US07/02780 filed Jan. 31,2007, both of which claim priority to U.S. Provisional PatentApplication Ser. No. 60/764,033 entitled “Method For The Reduction ofProtease Levels and Delivering Cationic Therapeutic Agents UsingWater-Soluble Polyanionic Oligomers & Polymers & Their Salts” filed Jan.31, 2006. The present patent application hereby incorporates each ofthese listed patent applications by reference in their entirety.

TECHNICAL FIELD

The disclosure relates generally to medical devices, barrier wounddressings, and methods for dressing wounds. More specifically,embodiments of the disclosure relate to surgical wound barrierdressings, including transcutaneous medical device, barrier dressings,antimicrobial adhesive barriers for surgical drapes, and antimicrobialadhesive barriers with absorbent surfaces, and processes for theirproduction and use, for controlling infections and/or preventing and/orminimizing protein drug degradation, for a drug such as insulin, at thesite of the delivery from an infusion set.

BACKGROUND

There are various types of surgical procedures that create surgicalwounds including investigative or corrective, minor or major, open(traditional) or minimal access surgery, elective or emergency, and/orincisions (simple cuts) or excision (removal of tissue). In each casesurgery exposes sub-cutaneous tissue; the resulting wound requiresmanagement to promote satisfactory healing and to avoid complicationssuch as infection. In the majority of cases this will require the use ofsome form of wound dressing. With ideal healing conditions, a surgicalwound, whether an incision or excision, will follow the normal woundhealing pathway associated with acute wounds. There are three acceptedmodes of healing. These include: Primary, Secondary, and tertiaryintention healing. Primary intention healing involves bringing the edgesof the wound together (in apposition) and securing them with sutures,clips or skin closure strips. These wounds usually seal within 24 to 48hours and generally heal within 8 to 10 days. Healing takes placethroughout the depth of the wound simultaneously and little new tissuehas to be formed. There may be a little leakage from the wound for thefirst 2 days; the presence of bloody exudate or odor beyond this is awarning sign of a potential complication. Managing the risks associatedwith the open phase of healing is a prime consideration. Secondaryintention healing requires that a wound is left open to allow healing bycontraction and replacement of missing tissue with granulation andepithelial tissue. It is common for surgical excisions or traumaticwounds with tissue loss to be healed this way. The healing duration willdepend on the amount of tissue that must be replaced and the resultingscar may be quite extensive. In tertiary intention healing, or delayedclosure the wound is kept open to allow for drainage of exudate, controlof contamination or for further surgical procedures to be completed. Ata later date (usually within 7 days as bacterial contamination risesmarkedly from the 8th day onwards), the patient returns to the operatingroom for the wound to be surgically closed. If the wound has to be keptopen for longer periods of time and there is significant bacterialcontamination; this has to be reduced before the wound is closed.

Infection is of major concern to most clinicians, institutions andpatients. Prior to the development of antiseptics (Lister ˜1860) andaseptic technique, infection rates following surgery were between 70%and 90% and 30% to 50% of these patients died as a consequence of thesewound infections. Fortunately this situation has improved, with typicalinfection rates of ˜10% being quoted in clinical literature. However,even surgical units applying the most advanced and thorough asepticprotocols rarely produce infection rates below a 5% average. Surgicalsite infection (SSI) occurs in an estimated 15% of clean surgeries and30% of contaminated surgeries. Plastic adhesive drapes with and withoutantimicrobial agents is a popular method of protecting the wound fromSSI, but conflicting results place their efficacy in question. Theembodiments disclosed herein can be used to improve the performance ofsurgical drapes.

The risk of infection is significantly higher in hospitals than in thehome environment because the patient may be in a state of reducedimmunity and may be exposed to micro-organisms against which an immuneresponse has not been prepared. The development of an infection adds asubstantial cost to treatment. A two-year, retrospective control studyundertaken at the Alfred Hospital determined that the incremental costattributable to surgical site infection after undergoing Coronary ArteryBypass Graft Surgery (CABG) was $12,419. The magnitude of theincremental cost was driven by an increase in the length of hospitalstay and the required drug therapy. Thus, infection is potentially aconsiderable financial drain on valuable patient care resources.

The risk of surgical incision complication is increased in certaincategories of patients including: the elderly or very young,immuno-compromised or immuno-suppressed, those with underlyingdebilitating disease, the nutritionally deprived, and those taking drugsand therapeutic treatments that reduce their ability to withstandinfection.

The literature recognizes the criteria for an effective post-operativedressing as possessing high moisture vapor permeability (MVP), lowadherence to the wound surface, absorbency, waterproof, or wash-prooffor minor surgery, bacterial barrier, conformable, non-sensitizing, goodadhesion to skin, sterile, low cost, non-flammable and non-toxic.

Transcutaneous medical devices are catheters, pins, implants and thelike which pass through the skin, are indwelling for some considerabletime, and reside inside and outside of the body during the course offunction. Transcutaneous medical devices include but are not limited tocentral venous catheters, peripheral venous catheters, Swan-Gauspulmonary catheters, central nervous system implants (ex. externalventricular drainage and ventricular reservoirs), peritoneal dialysiscatheters, such as for continuous ambulatory peritoneal dialysis andcontinuous cyclic peritoneal dialysis, hemodialysis catheters,transvenous pacemaker leads and temporary orthopedic pins.Transcutaneous medical devices, when in place, have a portion of thedevice which is external, that is which is left protruding from theskin, and which can be the cause of infection. The risk of acquiringinfections from transcutaneous devices is high. For instance, the riskof acquiring catheter-related bloodstream infection ranges from 0.9 to8%. These nosocomial bloodstream infections cause a case fatality ofmore than 20%, and account for an increase of thousands of dollars inhospital costs per infection, or tens of thousands of dollars persurvivor in ICU needing an extra week of hospital stay. As forperitoneal dialysis, a very experienced center today still has aperitonitis rate of one episode per 15 to 25 patient months. The majorsources of bacteria in these device-related infections are fromsurrounding skin.

Long-term transcutaneous devices such as catheters, certain biosensors,and infusion devices require patients to endure extended skin breaches(wounds) that can be difficult to manage clinically, i.e. infection andinflammation. These complications not only shorten device lifespan, butalso compromise patient health. In the case of short-term,transcutaneous glucose sensors, FDA has approved their usage for 3-7days for patients with diabetes. Infection can be an issue with theseshort-term sensors, although generally the sensors are removed prior tothe development of a full-blown infection. The ability to extend the invivo lifespan of these sensors from days to weeks can lower the cost ofsuch a therapy; however the longer these devices remain implanted, therisk of infection and hence adverse effects will increase. Adverseeffects seen at sites of transcutaneous device implantation, includingglucose sensors include infection, irritation, redness, itching andinflammation. Such adverse effects lead to shortened device lifespan invivo and in addition they can discourage patient involvement inimplantable sensors. Clearly, decreasing the risk of infections andinflammation at sensor implantation sites would likely not only increasesensor lifespan, but also decrease associated complications and adverseevents.

To prevent infections associated with transcutaneous medical devices andsurgical wounds, antiseptic preparation of insertion/incision sites, theinitial application of topical anti-microbial solutions such as alcoholor iodine to the insertion sites is known. For transcutaneous devices, afurther topical ointment after insertion of the device, such as anointment containing neomycin, polymyxin and bacitracin, has been shownto prevent catheter/device colonization/infection, but it may increasethe risk of fungal infections. For surgical incision sites, dressing thewound with an antimicrobial wound dressing such as a silver-based wounddressing is known. Ointments may be inconvenient depending upon the typeof wound as a consequence of having to continually apply a dosing andthe difficulty associated with being able to view the wound forassessment, i.e. requiring multiple replacements or having to clean thewound prior to evaluation. There have also been attempts to preventinfection at the site by the addition of an antimicrobial cuff to thecatheters at or below the entry point, i.e. with an anti-microbial agentimpregnated in the cuff. Efforts to coat the catheters withanti-microbial agents are known. However, these efforts have failed inclinical trials. Presently, the most common catheter dressing used inhospitals comprises sterile gauze or polyurethane film, both which havelimited infection control properties. Efforts to replace gauze with atransparent film dressing to allow a visual check on the insertion siteare known, see for instance U.S. Pat. No. 5,372,589, issued Dec. 13,1994 to Davis. No anti-microbial control is taught with such a dressing.Johnson & Johnson Medical Inc. markets a product under the trademarkBIOPATCH®, a chlorhexidine gluconate-impregnated polyurethane spongecatheter patch.

An iodophor transparent dressing has also been suggested. However, todate, no completely effective anti-microbial device for use withtranscutaneous medical devices is known. A layered antimicrobial devicefor securing transcutaneous devices is described by Burrell et al. inU.S. Pat. No. 7,137,968.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the disclosure are described below with reference to thefollowing accompanying drawings.

FIG. 1 is a medical device according to an embodiment of the disclosure.

FIG. 2 is a medical device applied to a patient according to anembodiment of the disclosure.

FIG. 3 is a schematic sectional of a medical device such as a conformalsurgical wound device barrier (island) dressing where the wound contactlayer is fabricated from an absorbent material and the surroundingsilicone gel barrier is formulated to include an antimicrobial agent,according to an embodiment of the disclosure.

FIGS. 4A and 4B are schematic sectionals of a medical device such as anantimicrobial adhesive “frame” barrier for placement around a surgicalsite. The barrier can be a three-layer construct comprising a topabsorbent layer, a tacky silicone gel barrier formulated to include anantimicrobial agent, and a release liner that can be removed just priorto application, according to an embodiment of the disclosure.

FIG. 5 is a representation of a medical device such as a surgicalbarrier border placed on a patient's abdomen prior to a surgicalprocedure, according to an embodiment of the disclosure.

FIGS. 6A, 6B, and 6C are schematic sectionals of a medical device suchas an island dressing including a flexible impervious layer and highsurface area fabric composite beneath a tacky silicone gel layer with anabsorbent “island” pad and release liner upper layer, according to anembodiment of the disclosure.

FIG. 7 is a schematic of a representative process flow that will allowfor high volume production of a medical device in accordance withembodiments of the present disclosure.

FIG. 8 is a schematic sectional figure of a medical device such as atwo-layer transcutaneous device dressing in accordance with embodimentsof the present disclosure.

FIG. 9 is a schematic perspective view of a medical device such as athree-layer transcutaneous device composed of a cover and base mountedon opposite sides of a common substrate to form a top securing layer anda bottom dressing showing the opening for placement around thetranscutaneous medical device, according to an embodiment of thedisclosure.

FIG. 10 is a schematic perspective view of the device of FIG. 9 inanother configuration, according to an embodiment of the disclosure.

FIG. 11 is a schematic cross sectional figure of a two-layertranscutaneous device dressing in place with a catheter penetrating theskin of a patient, according to an embodiment of the disclosure.

FIG. 12 is a schematic sectional of a two-component, two layertranscutaneous device dressing where the inner component is fabricatedfrom a silicone gel formulated to contain a water absorbing materialaccording to an embodiment of the disclosure.

FIG. 13 is a plan view of the transcutaneous device barrier dressingslid in place with a biosensor surrounded by a single dressing, suchthat the dressing is in contact with a portion of the sensor protrudingfrom the skin according to an embodiment of the disclosure.

FIG. 14 is a plan view of the transcutaneous device dressing, accordingto an embodiment of the disclosure, showing the slit in the lowerdressing.

FIG. 15 is a schematic perspective view of a three-layer transcutaneousdevice composed of a cover and base, with the lower skin contacting baseincluding an inner insert of a water absorbing material and portionsmounted on opposite sides of a common substrate to form a top securinglayer and a bottom dressing showing the opening for placement around thetranscutaneous medical device, according to an embodiment of thedisclosure.

FIG. 16 is a chlorhexidine diacetate release profile (10% loading insilicone gel), according to an embodiment of the disclosure.

FIG. 17 is a polyhexanide hydrochloride release profile (10% loaded insilicone gel), according to an embodiment of the disclosure.

FIG. 18 is a polyhexanide hydrochloride release profile (10% loading insilicone gel with 10% polyvinylpyrrolidone blended into the silicone),according to an embodiment of the disclosure.

FIG. 19 is a chlorhexidine diacetate release profile (10% loading insilicone gel with 10% carboxymethylcellulose blended into the silicone),according to an embodiment of the disclosure.

FIG. 20 is a representation of the zones of clearance for 10, 15, & 20%chlorhexidine diacetate loaded Momentive Performance Materials UV-curedsilicone gel, according to an embodiment of the disclosure.

FIG. 21 is a representation of the zones of clearance for 15% and 10%octenidine dihydrochloride loaded Nusil MED 6345 with A and B partratios of 50:50, 45:55 respectively, and 10% octenidine loading in a50:50 formulation and 0.5% and 10% polyhexanide hydrochloride with A andB part ratios of 50:50 each. FIG. 19 is a representation of the zones ofclearance against Staphylococcus epidermidis (ATCC 12228) for 1. 15%octenidine dihydrochloride (1:1, A:B), 2. 10% octenidine dihydrochloridein Med 6345 (0.9:1.1, A:B), 3.10% octenidine dihydrochloride (1:1, A:B),4. 0.5% PHMB (1:1, A:B), and 5. 10% PHMB (1:1, A:B) all formulated inNusil Med 6345. FIG. 20 is a representation of the zones of clearanceagainst Staphylococcus aureus (clinical isolate) for 1. 15% octenidinedihydrochloride (1:1, A:B), 2. 10% octenidine dihydrochloride in Med6345 (0.9:1.1, A:B), 3.10% octenidine dihydrochloride (1:1, A:B), 4.0.5% PHMB (1:1, A:B), and 5. 10% PHMB (1:1, A:B) all formulated in NusilMed 6345. FIG. 22 is is a representation of the zones of clearance for15% and 10% octenidine dihydrochloride loaded Nusil MED 6345 with A andB part ratios of 50:50, 45:55 respectively, and 10% octenidine loadingin a 50:50 formulation and 0.5% and 10% polyhexanide hydrochloride withA and B part ratios of 50:50 each. FIG. 19 is a representation of thezones of clearance against Staphylococcus aureus (ATCC 12228) for 1. 15%octenidine dihydrochloride (1:1, A:B), 2. 10% octenidine dihydrochloridein Med 6345 (0.9:1.1, A:B), 3.10% octenidine dihydrochloride (1:1, A:B),4. 0.5% PHMB (1:1, A:B), and 5. 10% PHMB (1:1, A:B) all formulated inNusil Med 6345. FIG. 20 is a representation of the zones of clearanceagainst Staphylococcus aureus (clinical isolate) for 1. 15% octenidinedihydrochloride (1:1, A:B), 2. 10% octenidine dihydrochloride in Med6345 (0.9:1.1, A:B), 3.10% octenidine dihydrochloride (1:1, A:B), 4.0.5% PHMB (1:1, A:B), and 5. 10% PHMB (1:1, A:B) all formulated in NusilMed 6345.

DESCRIPTION

This disclosure is submitted in furtherance of the constitutionalpurposes of the U.S. Patent Laws “to promote the progress of science anduseful arts” (Article 1, Section 8).

Applicant has recognized numerous shortcomings of current securingdevices. For example, a securing device is taught for affixing anintravenous device to the body in U.S. Pat. No. 3,918,446, issued Nov.11, 1975 to Buttaravoli. The device has an upper and a lower pad,between which the intravenous device is fixed. Since the function of thedevice is to secure the device to the body, there is a teaching toprovide an adhesive material to the bottom of lower pad, and to thebottom of the top pad. There is a mention of providing the adhesive withan antibacterial agent.

This device has the disadvantage of using adhesives with theantibacterial agent, which generally limits the effectiveness and longlasting ability of the antibacterial agent. Furthermore, the adhesivecan be irritating next to the skin, cause skin damage and patientdiscomfort on removal, and inhibits the removal or changing of thedevice. Furthermore, many adhesives that are placed onto the surface ofa matrix aimed at the delivery of an active pharmaceutical ingredient(API) can act as a moisture barrier, which can limit the effectivenessof the API because moisture generally facilitates the delivery of theAPI by first dissolving the API and subsequently aiding the release ofthe API from the material which has been placed at the site of interest,i.e. the site of transcutaneous device implantation. The term agent andingredient may be used interchangeably herein.

The disclosed dressing is a waterproof, conformable dressing formulatedwith or without any variety of active pharmaceutical ingredients (suchas an antimicrobial agent, antiproteolytic agent, or oligodynamic metal,and/or mixtures of thereof), the bulk dressing material possessingappreciable tack (and as such does not require the use of a secondaryadhesive layer, although one can be used if desired) that will notdamage epithelium upon removal, is easily constructed with or without anabsorbent pad to collect wound exudate, and creates a seal (barrier)around the entire wound to limit any infiltration of invading pathogensto the incision site.

Embodiments of the device of the present disclosure can provide a skinfriendly, conformal, tacky & self adhesive silicone gel constructcompounded with an antimicrobial agent. The device can also include aprotective top layer that acts as an adhesion layer in some embodiments,a peel away release liner, and a slit through the dressing exposingaccess to a central cutout that allows placement of the barrier dressingon the skin and below the transcutaneous device when in place thusallowing the transcutaneous device to remain in contact with the skin toprovide a conformal antimicrobial barrier surrounding the device andtherefore limiting the likelihood of infection of the device or thetissue surrounding the device. In one embodiment, the transcutaneousdevice dressing barrier is secured around the device and a secondsimilar barrier device mounted on the opposite side of the protectivebarrier is secured over the top of the protruding transcutaneous device(such as a catheter) and to the top (protective) layer. In the case of asurgical wound dressing barrier device, a skin friendly, conformal,tacky & self adhesive silicone gel construct compounded with anantimicrobial agent. The dressing also includes a protective top layerthat acts as an adhesion layer in some embodiments, a peel away releaseliner, and an absorbent pad in the center of the dressing (island)allows placement of the barrier dressing on the skin surrounding thesurgical wound in order to provide a conformal antimicrobial barriersurrounding the wound and therefore limiting the likelihood of infectionof the wound. In one embodiment, the surgical wound dressing barrier issecured around the wound and the absorbent material is in direct contactwith the closed or open surgical wound, abrasion, or penetrating injury.In the case of a dry wound, a tacky silicone wound dressing barrierwithout an absorbent “island” can be utilized in order to protect thewound from external insult and invading pathogens.

Barrier wound dressings of the disclosure can include a first tackysilicone gel polymer interfacial adhesion layer formulated to include atleast one active pharmaceutical agent are provided.

Barrier wound dressings and antimicrobial barrier adhesives including afirst tacky silicone gel polymer interfacial adhesion layer to includean active pharmaceutical agent wherein said active pharmaceutical agentcan include an antibacterial agent, anti-inflammatory agent, nutrient,antibiotic agent, healing agent, antiproteolytic agent, anestheticagent, oligodynamic metal, are provided.

Tacky silicone gel polymer interfacial adhesion layers incorporating anactive pharmaceutical agent of organic, organometallic, or metallicnature comprising one or more of an antimicrobial agent, antibioticagent, anti-inflammatory agent, antiproteolytic agent, anesthetic agent,nutritional agent, healing agent, coagulation agent, anticoagulationagent, oligodynamic metal, moisturizing agent, or an angiogenesisstimulating agent are provided.

Barrier wound dressings including tacky silicone gel polymer interfacialadhesion layers formulated to include at least one active pharmaceuticalagent are provided.

Barrier wound dressings including a first tacky silicone gel polymerinterfacial adhesion layer including an active pharmaceutical agentwherein said active pharmaceutical agent can include one or more of anantibacterial agent, anti-inflammatory agent, nutrient, antibioticagent, healing agent, or anesthetic agent are provided.

Single dressing barrier wound dressings including a single tackysilicone gel polymer interfacial adhesion layer adapted for applicationupon a tissue surface and surrounding the medical device at the locationwhere the device breaches the body surface modified to include a centralinner absorbent material component formulated to include at least oneactive pharmaceutical agent are provided.

Also provided are barrier wound dressings including a single tackysilicone gel polymer interfacial adhesion layer adapted for applicationupon a tissue surface and encompassing a surgically created incisionsite whereby a non-adherent, fluid-absorbing layer is in contact withthe closed, or open, incision, and the conformal “tacky” siliconeinterfacial adhesion layer is adhered to skin surrounding the surgicalwound. The silicone interfacial adhesion layer may be formulated toinclude at least one active pharmaceutical agent or one of manynon-active compounds that may aid in the healing of the surgical wound.It is understood that dressings created for the purposes of dressingsurgical wounds can be used to dress wounds resulting from injury ortrauma.

Surgical site barriers including a single tacky silicone gel polymerinterfacial layer comprising a top (upper) layer of high surface areamaterial for the absorbance of fluids are provided in roll format andthe conformal “tacky” silicone layer can be adhered to the skinsurrounding the site where the surgery may be conducted. The siliconeinterfacial adhesion layer may be formulated to include at least oneactive pharmaceutical agent or one of many non-active compounds that mayaid in preventing bacterial infiltration of the surgical wound.

The devices and methods of the present disclosure are described withreferences to FIGS. 1-22. Referring first to FIG. 1, a medical device 10is shown that includes a substrate 12 having one surface 16 and anotheropposing surface 18. On the one surface 16 is a composition 14comprising a silicone material and at least one pharmaceutically activeagent.

In accordance with example implementations, the silicone material can bea tacky silicone material. Silicone is a polymer comprising siloxaneunits such as the dimethylsiloxane variety. The silicone material can bea gel having “tack” consistent with the amount of cross linking unitspresent in the material. Generally, medical grade silicones are cured byone of three mechanisms. These include: 1. Room temperaturevulcanization (RTV) which is either a single component silicone rubberprecursor that can utilized condensation-type chemistry involving theloss of acetic acid during cure or as platinum catalyst-based additionchemistry; 2. Peroxide catalyzed vulcanization whereby two componentsare combined (one containing the catalyst) where the catalyst is aperoxide, such as benzoyl peroxide, which initiates a free radicalreaction for vulcanization/crosslinking of the two components with theaddition of heat; and 3. Platinum complex-mediated (addition cure)rubber that requires compounding of two components and heating orirradiating the rubber mixture to drive the reaction to completion.

The pharmaceutically active agent can be one or more of an antibacterialagent, anti-inflammatory agent, nutrient, antibiotic agent, healingagent, antiproteolytic agent, anesthetic agent, oligodynamic metalagent, coagulation agent, anticoagulation agent, moisturizing agent,and/or angiogenesis stimulating agent.

Antimicrobial agent can be a term for drugs, chemicals, or othersubstances that either kill or slow the growth of microbes. Among theantimicrobial agents are antibacterial drugs, including antibiotics,antiviral agents, antifungal agents, organometallic compounds such assilver carbenes, anti parasitic drugs, and oligodynamic metals toinclude silver and the like. Antibiotics are commonly classified basedon their mechanism of action, chemical structure, or spectrum ofactivity. Most antibiotics target bacterial functions or growthprocesses. Antibiotics that target the bacterial cell wall (penicillins,cephalosporins), or cell membrane (polymoxins), or interfere withessential bacterial enzymes (quinolones, sulfonamides) are usuallybactericidal in nature. Those that target protein synthesis, such as theaminoglycosides, macrolides, and tetracyclines, are usuallybacteriostatic. Further categorization is based on their targetspecificity: “Narrow-spectrum” antibiotics target particular types ofbacteria, such as Gram-negative or Gram-positive bacteria, whereasbroad-spectrum antibiotics affect a wide range of bacteria. In the lastfew years, three new classes of antibiotics have been brought intoclinical use. This follows a 40-year hiatus in discovering new classesof antibiotic compounds. These new antibiotics are of the followingthree classes: cyclic lipopeptides (daptomycin), glycyclines(tigecycline), and oxazolidinones (linezolid). Tigecycline is abroad-spectrum antibiotic, whereas the two others are used forGram-positive infections. These developments show promise as a means tocounteract the bacterial resistance to existing antibiotics.

The antimicrobial agent can include an “Anti-microbial metal” which canbe metals whose ions have an anti-microbial effect. “Metal” or “metals”includes one or more metals whether in the form of substantially puremetals, alloys or compounds including oxides, and salts such asnitrides, borides, sulphides, halides, carboxylates, or hydrides. Themetal may also be biocompatible. Anti-microbial metals include Ag, Au,Pt, Pd, Ir, Ga (i.e. the noble metals), Sn, Cu, Sb, Bi, Ce, and Zn.Atoms, ions, molecules or clusters of the anti-microbial metal (hereinafter “species” of the anti-microbial metal) can have “Anti-microbialeffect” when they are released.

The antimicrobial agent can be one or more of chloroxylenol(parachlorometaxylenol), acedapsone; acetosulfone sodium; alamecin;alexidine; amdinocillin; amdinocillin; pivoxil; amicycline; amifloxacin;amifloxacinmesylate; amikacin; amikacin sulfate; aminosalicylic acid;aminosalicylate sodium; amoxicillin; amphomycin; ampicillin; ampicillinsodium; apalcillin sodium; apramycin; aspartocin; astromicin sulfate;avilamycin; avoparcin; azithromycin; azlocillin; azlocillin sodium;bacampicillin hydrochloride; bacitracin; bacitracin,methylenedisalicylate; bacitracin zinc; bambermycins; benzoylpascalcium; berythromycin; betamicin sulfate; biapenem; biniramycin;biphenamine hydrochloride; bispyrithionemagsulfex; butikacin; butirosinsulfate; capreomycin sulfate; carbadox; carbenicillin disodium;carbenicillin, indanyl sodium; carbenicillin phenyl sodium;carbenicillin potassium; carumonam sodium; cefaclor; cefadroxil;cefamandole; cefamandolenafate; cefamandole sodium; cefaparole;cefatrizine; cefazaflur sodium; cefazolin; cefazolin sodium;cefbuperazone; cefdinir; cefepime; cefepime hydrochloride; cefetecol;cefixime; cefmenoxime hydrochloride; cefmetazole; cefmetazole sodium;cefonicid monosodium; cefonicid sodium; cefoperazone sodium; ceforanide;cefotaxime sodium; cefotetan; cefotetan disodium; cefotiamhydrochloride; cefoxitin; cefoxitin sodium; cefpimizole; cefpimizolesodium; cefpiramide; cefpiramide sodium; cefpirome sulfate; cefpodoxime;proxetil; cefprozil; cefroxadine; cefsulodin sodium; ceftazidime;ceftibuten; ceftizoxime sodium; ceftriaxone sodium; cefuroxime;cefuroximeaxetil; cefuroximepivoxetil; cefuroxime sodium; cephacetrilesodium; cephalexin; cephalexin hydrochloride; cephaloglycin;cephaloridine; cephalothin sodium; cephapirin sodium; cephradine;cetocycline hydrochloride; cetophenicol; chloramphenicol;chloramphenicolpalmitate; chloramphenicolpantothenate complex;chloramphenicol sodium succinate; chlorhexidinephosphanilate;chlorhexidinediacetate, chlorhexidinedihydrochloride,chlorhexidinedigluconate, chlortetracycline bisulfate; chlortetracyclinehydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin hydrochloride;cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin;clindamycin hydrochloride; clindamycinpalmitate hydrochloride;clindamycin phosphate; clofazimine; cloxacillinbenzathine; cloxacillinsodium; cloxyquin; colistimethate sodium; colistin sulfate; coumermycin;coumermycin sodium; cyclacillin; cycloserine; dalfopristin; dapsone;daptomycin; demeclocycline; demeclocycline hydrochloride; demecycline;denofungin; diaveridine; dicloxacillin; dicloxacillin sodium;dihydrostreptomycin sulfate; dipyrithione; dirithromycin; doxycycline;doxycycline calcium; doxycyclinefosfatex; doxycyclinehyclate; droxacinsodium; enoxacin; epicillin; epitetracycline hydrochloride;erythromycin; erythromycin acistrate; erythromycin estolate;erythromycin ethylsuccinate; erythromycin gluceptate; erythromycinlactobionate; erythromycin propionate; erythromycin stearate; ethambutolhydrochloride; ethionamide; fleroxacin; floxacillin; fludalanine;flumequine; fosfomycin; fosfomycintromethamine; fumoxicillin; furazoliumchloride; furazoliumtartrate; fusidate sodium; fusidic acid; ganciclovirand ganciclovir sodium; gentamicin sulfate; gloximonam; gramicidin;haloprogin; hetacillin; hetacillin potassium; hexedine; ibafloxacin;imipenem; isoconazole; isepamicin; isoniazid; josamycin; kanamycinsulfate; kitasamycin; levofuraltadone; levopropylcillin potassium;lexithromycin; lincomycin; lincomycin hydrochloride; lomefloxacin;lomefloxacin hydrochloride; lomefloxacinmesylate; loracarbef; mafenide;meclocycline; meclocyclinesulfosalicylate; megalomicin potassiumphosphate; mequidox; meropenem; methacycline; methacyclinehydrochloride; methenamine; methenamine hippurate; methenaminemandelate; methicillin sodium; metioprim; metronidazole hydrochloride;metronidazole phosphate; mezlocillin; mezlocillin sodium; minocycline;minocycline hydrochloride; mirincamycin hydrochloride; monensin;monensinsodiumr; monovalent silver salts, nafcillin sodium; nalidixatesodium; nalidixic acid; natainycin; nebramycin; neomycin palmitate;neomycin sulfate; neomycin undecylenate; netilmicin sulfate;neutramycin; nifuiradene; nifuraldezone; nifuratel; nifuratrone;nifurdazil; nifurimide; nifiupirinol; nifurquinazol; nifurthiazole;nitrocycline; nitrofurantoin; nitromide; norfloxacin; novobiocin sodium;octenidinedihydrochloride, octenidinediacetate, octenidinedigluconate,ofloxacin; onnetoprim; oxacillin and oxacillin sodium; oximonam;oximonam sodium; oxolinic acid; oxytetracycline; oxytetracyclinecalcium; oxytetracycline hydrochloride; paldimycin; parachlorophenol;paulomycin; pefloxacin; pefloxacinmesylate; penamecillin; penicillinssuch as penicillin g benzathine, penicillin g potassium, penicillin gprocaine, penicillin g sodium, penicillin v, penicillin v benzathine,penicillin v hydrabamine, and penicillin v potassium; pentizidonesodium; phenyl aminosalicylate; piperacillin sodium; pirbenicillinsodium; piridicillin sodium; pirlimycin hydrochloride; pivampicillinhydrochloride; pivampicillinpamoate; pivampicillinprobenate;

polyhexamethylenebiguanide (polyhexanide hydrochloride, PHMB); polymyxinb sulfate; porfiromycin; propikacin; pyrazinamide; pyrithione zinc;quindecamine acetate; quinupristin; racephenicol; ramoplanin; ranimycin;relomycin; repromicin; rifabutin; rifametane; rifamexil; rifamide;rifampin; rifapentine; rifaximin; rolitetracycline; rolitetracyclinenitrate; rosaramicin; rosaramicin butyrate; rosaramicin propionate;rosaramicin sodium phosphate; rosaramicinstearate; rosoxacin; roxarsone;roxithromycin;

sancycline; sanfetrinem sodium; sarmoxicillin; sarpicillin; scopafungin;silver acetate; silver nitrate, nanocrystalline silver, silverpolystyrene sulfonate (cross-linked” and non-cross-linked); silvercarboxymethyl cellulose, silver polysaccharides (such as silverchondroitin sulfate and the like), silver carbene compounds, sisomicin;sisomicin sulfate; sparfloxacin; spectinomycin hydrochloride;spiramycin; stallimycin hydrochloride; steffimycin; streptomycinsulfate; streptonicozid; sulfabenz; sulfabenzamide; sulfacetamide;sulfacetamide sodium; sulfacytine; sulfadiazine; sulfadiazine sodium;sulfadiazine silver; sulfadoxine; sulfalene; sulfamerazine; sulfameter;sulfamethazine; sulfamethizole; sulfamethoxazole; sulfamonomethoxine;sulfamoxole; sulfanilate zinc; sulfanitran; sulfasalazine;sulfasomizole; sulfathiazole; sulfazamet; sulfisoxazole; sulfisoxazoleacetyl; sulfisboxazolediolamine; sulfomyxin; sulopenem; sultamricillin;suncillin sodium; talampicillin hydrochloride; teicoplanin; temafloxacinhydrochloride; temocillin; tetracycline; tetracycline hydrochloride;tetracycline phosphate complex; tetroxoprim; thiamphenicol;thiphencillin potassium; ticarcillincresyl sodium; ticarcillin disodium;ticarcillin monosodium; ticlatone; tiodonium chloride; tobramycin;tobramycin sulfate; tosufloxacin; trimethoprim; trimethoprim sulfate;trisulfapyrimidines; troleandomycin; trospectomycin sulfate;tyrothricin; vancomycin; vancomycin hydrochloride; virginiamycin and/orzorbamycin.

Antimicrobials can be biocompatible when the toxicity that isdemonstrated is tolerable for the intended utility. Thus, for humanutility, biocompatible can be acceptably toxic or non-toxic to humans orhuman tissues.

One of the most common methods of measuring anti-microbial effect is bythe Kirby-Bauer method. The Kirby-Bauer method measures the zone ofinhibition (ZOI) created when the material is placed on a bacterial lawngrown onto agar. A relatively small or no ZOI (ex. less than 1 mm)indicates either a non useful anti-microbial effect or low solubility ofthe active agent in the media of study, while a larger ZOI (ex. greaterthan 5 mm) indicates a highly useful anti-microbial effect. Oneprocedure for a ZOI test is set out in the Examples which follow.

“Sustained release” or “sustainable basis” are used to define release ofatoms, molecules, ions or clusters of an anti-microbial metal thatcontinues over time measured in hours or days, and thus distinguishesrelease of such metal species from the bulk metal, which release suchspecies at a rate and concentration which is too low to achieve ananti-microbial effect, and from highly soluble salts of anti-microbialsalts such as silver nitrate, or less soluble silver salts such assilver acetate, or highly soluble antimicrobial (organic species) suchas polyhexamethylene biguanide dihydrochloride (PHMB or polyhexanide),or organic species with lower solubility that include chlorhexidinediacetate, octenidine dihydrochloride, or more complex salts such asoctenidine polystyrene sulfonate, polyhexamethylene biguanidepolystyrene sulfonate, polyhexamethylene biguanide carboxymethylcellulose, or octenidine carboxymethyl cellulose.

The pharmaceutical agent can be an anti-inflammatory agent. Theanti-inflammatory agent can be one or more of hydrocortisone,hydroxyltriamcinolone, alphamethyldexamethasone, dexamethasone-sodiumphosphate, dexamethasone; beclomethasone dipropionate,clobetasolvalerate, desonide, desoxymethasone, desoxycorticosteroneacetate, dexamethasone, dichlorisone, diflorasonediacetate,diflucortolonevalerate, fluadrenolone, fluclaroloneacetonide,fludrocortisone, flu methasonepivalate, fluosinoloneacetonide,fluocinonide, flucortinebutylester, fluocortolone, fluprednidene(fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisoneacetate, hydrocortisone butyrate, methylprednisolone,triamcinoloneacetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosonediacetate, fluradrenaloneacetonide,medrysone, amc, amcinafide, betamethasone and the balance of its esters,chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone,dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone,fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylproprionate, hydrocortamate, meprednisone, paramethasone,prednisolone, prednisone, beclomethasonedipropionate,betamethasonedipropionate, triamcinolone prostaglandin H synthetaseinhibitors (Cox I or Cox II), flurbiprofen, ketorolac, suprofen,nepafenac, amfenac, indomethacin, naproxen, ibuprofen, bromfenac,ketoprofen, meclofenamate, piroxicam, sulindac, mefanamic acid,diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome,etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, HCT-1026,NCX-284, NCX-456, tenoxicam, carprofen, cyclooxygenase type II selectiveinhibitors, vioxx, celecoxib, P54, etodolac, L-804600, S-33516; PAFantagonists, A-137491, ABT-299, apafant, bepafant, minopafant, E-6123,BN-50727, nupafant, modipafant, PDE IV inhibitors, ariflo, torbafylline,rolipram, filaminast, piclamilast, cipamfylline, CG-1088, V-11294A,CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636,BAY-19-8004, and/or roflumilast.

The active pharmaceutical agent can be an antiproteolytic agent. Theantiproteolytic agent can be one or more of amprenavir (Agenerase),fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir(Kaletra), ritonavir (Norvir), saquinavir (Fortovase), and nelfinavir(Viracept), salts of ethylene diamine tetracetic acid, salts ofpolystyrene sulfonate, and sulfated oligo & polysaccharides.

Composition 14 can comprise from about 60 to about 99 (wt/wt %) siliconematerial; from about 1 to about 40 (wt/wt %) pharmaceutical agent.Composition 14 can be prepared before partial or complete curing of thesilicone material. Composition 14 can be prepared as part of the curingof the silicone material. Composition 14 can be prepared upon partial orcompletion of the curing of the silicone material.

Medical device 10 may be configured as a wound dressing. Composition 14may be an adhesive mixture bound to substrate 12. The adhesive mixturecan be a tacky silicone material and at least one active pharmaceuticalagent. The adhesive mixture can be conformal and/or pressure sensitive.

Substrate 12 can be substantially planar. Substrate 12 can be a flexiblefabric such as one or both of knitted and non-woven fabric. Substrate 12can be cellulosic such as one or both of cotton or wool. Substrate 12can be a polymeric material. The polymeric material can be one or bothof woven or a film. Substrate 12 can be one or more of a polyurethane,polyalkylene, polysiloxane, polyester, and/or polyamide. Substrate 12can be a fenestrated film material.

In accordance with example embodiments, composition 14, configured as anadhesive mixture, for example, can extend around the perimeter of thesubstrate. Substrate 12 can define an opening extending between theperiphery of the plane of the substrate. The substrate can define anopening extending from an edge of the plane inwardly to a point awayfrom the edge. The adhesive mixture may extend around the perimeter ofthe opening.

Alternate compositions and/or configurations of the devices of thepresent disclosure, including various anti-microbial formulations ofcomposition 14 used in the devices are set out in further detail below.

As an example, composition 14 can be formed of an tacky silicone gelsuch as Nusil Technologies MED 6345 (platinum curing silicone elastomer)and substrate 12 may be formed of a high surface area, porous,non-adherent material such as a woven, non-woven, or fenestrated filmmaterial, fabric such as cotton, gauze, a polymeric netting or mesh suchas polyethylene, nylon, polypropylene or polyester, an elastomer such aspolyurethane or block copolymer elastomers such as Kraton, or a foamsuch as open cell polyurethane foam. Example woven meshes may be formedfrom polyester, acetate, or cotton gauze. One example, hydrophilicpolyurethane foam is HYPOL™, available from W. R. Grace & Co., New York,N.Y., USA.

An absorbent material for use in the devices of the disclosure such aspart of composition 14 or as a separate a wound contact layer or assubstrate 12 such as an upper surface of a surgical site antimicrobialframe, or around transcutaneous devices such as a super-pubic catheterwhere leaking urine may be absorbed and held away from the skin whereotherwise it can cause irritation and maceration, is a non-wovenrayon/polyester core such as SONTARA™ 8411, a 70/30 rayon/polyesterblend commercially available from Dupont Canada, Mississauga, Ontario,Canada. This product is sold by National Patent Medical as an AmericanWhite Cross sterile gauze pad. However, other suitable absorbentmaterials include woven or non-woven materials, non-woven such asEvolon® spun bond polyester being preferred given the ability to absorbup to 400% of its own weight in liquid as a consequence of the highsurface area. The material may be made from fibers such as rayon,polyester, rayon/polyester, polyester/cotton, cotton and cellulosicfibers. Creped cellulose wadding, an air felt of air laid pulp fibers,cotton, gauze, and other well known absorbent materials suitable formedical dressings can be utilized. Other absorbent materials which maybe used for the inner portions of the barrier dressing device includefoamed materials (synthetic and biopolymers), hydrogels, absorbentpolymers such as hydrocolloids to include any variety known in the woundhealing art including carboxymethylcellulose (CMC), alginates, collagen,hydrophilic polyurethanes, crosslinked acrylic polymers, crosslinkedpolyethylene glycol, silicone gel blends that incorporate absorbentpolymers such as poly(vinylpyrrolidone) (PVP), polyethylene glycol(PEG), carboxymethylcellulose (CMC), alginates, or a commerciallyavailable hydrocolloid wound dressing such as Carra Colloid (CarringtonLaboratories). These absorbent materials may also be formulated toinclude an active pharmaceutical ingredient such as an antimicrobialagent (e.g. chlorhexidine) or a healing aid such as vitamin E and theabsorbent material may be connected to the bulk dressing (silicone gel)material in at least two ways that include as an island situated uponthe silicone gel or recessed into the silicone gel.

Referring to FIG. 2, device 10 can be applied to epidermal layer 22 ofpatient 20 for example. Layer 22 may or may not include a laceration,ulcer, or other epidermal breach. Device 10 can be applied to layer 22contacting composition 14 with layer 22 as part of a method for dressingwound for example. Of course device 10 may be applied to layer 22 forother reasons, including but not limited to post or pre surgical, orprophylatically for example. In accordance with one method, substrate 12can be adhered to layer 22 using composition 14.

Referring to FIG. 3, a device 32 is shown configured as a surgical woundbarrier dressing. Device 32 can include composition 14 configured as asilicone gel component 34 having a release liner 36 attached thereto.Device 32 can include a fluid absorbing portion bound to the substratesuch as an absorbent layer 38 on the surface of component 34 opposingthe surface having release liner 36 attached thereto. Absorbent layer 38may take the form of an island above component 34 and/or may be attachedto component 34 with an interfacial layer 40. The absorbent layer can bea hydrocolloid for example and may be part of composition 14 forexample.

Referring to FIGS. 4A and 4B, in accordance with an alternativeembodiment, devices 50 and 60 are shown than can be configured as aninsert and frame. Devices 50 and 60 can be configured as anantimicrobial surgical barrier that may be implemented as part of asurgical drape or may be used alone. FIG. 5 is a representation of thesurgical barrier placed on the abdomen prior to a surgical procedure.Device 70 is represented as a pictorial representation of the barrier isapplied to the abdomen, for example. In accordance with exampleimplementations, devices 50 and 60 can be constructed of composition 14configured as a tacky silicone gel layer 54 and 64, respectively. Theselayers 54 and 64 may have release liners 56 and 66 on one side andsubstrate 52 and 62 on the opposing side. Device 50 may be used as asurgical tape to confine dressings for example, and device 60 may beused to define a barrier for a surgical procedure.

Referring to FIGS. 6-7, another embodiment of a medical device is shownas well as a process flow for producing same. Referring to FIGS. 6A-6C,device 80 is configured as a disk or puck. Device 80 can include acomposition 14 configured as a silicone gel component 86 having arelease liner 90 on one surface and substrate 12 configured as a fabricmaterial 84 on the opposing surface. Device 80 can further include andan impervious flexible layer 82 on the opposing surface of fabricmaterial 84. Device 80 can define a base 92 having an island 94extending therefrom. Base 92 can include at least silicone gel component86 and fabric material 84. Island 94 can extend from silicone gelcomponent 86 and/or include an absorbent material 88. Island 94 caninclude release liner 90, and release liner 90 may be continuous fromthe one surface of silicone gel component 86 to an opposing surface ofabsorbent material 88. Alternatively, silicone gel component 86 can becured as a sheet in a mold where release is facilitated easily andfabric layer 84 added to the surface. The fabric silicone composite canbe turned 180 degrees and absorbent material layer 88 added. Shapes ofthe device can be die cut from the sheet as desired.

Referring to FIG. 7 a process flow for preparing device 80 is shown withthe materials being consistent with those described in FIGS. 6A-6C. Inthe fabrication of such devices it can be beneficial to dispense theuncured silicone gel mixture over a composite substrate that includes abottom layer impervious to a silicone liquid composition ready for cureand comprising a thin flexible material such as a polymer such aspolyurethane and a second layer in contact with the first imperviouslayer comprising a high surface area material such as a polyester fabric(woven or non-woven). When cured this composition can remain flexibleand the gel can be further modified to include an absorbent componentand covered with a release liner, for example. The following method canalso be applied to scaling up to produce island dressings or similar5-layer configurations.

In accordance with a specific example, a platinum catalyzed 2-componentsystem can be utilized such as Med 6345 (Nusil, of Carpenteria Calif.),comprising parts A and B which are generally combined in equalproportions (50:50 w/w) and a known quantity of the finely dividedantimicrobial agent is added and the mixture combined with the aid of aspatula or by using an automated mixing apparatus such as a SpeedMixer.In practice, the antimicrobial agent may be combined with one of theconstituents (part A or B) and mixed to a fine consistency before addingthe second part or as a kit for storage and use at a later time. Thematerial is cast onto a release liner, such as a polyethylene or afluoropolymer for example and into a mold and the silicone mixturegently leveled by the use of a spatula. The barrier dressing formulationis cast onto a release liner within a curing “tool” (mold) and the toolis placed in a convection oven set at 80° C. and the formulation curedfor a period of 2-3 hours to yield a tacky gel substrate with a releaseliner affixed to one side. The protective layer is subsequently pressedonto the available silicone gel surface and the protective layer isretained by contact adhesion. By using a slight excess of part B, suchas a 55:45 w/w of part B to part A, the gel may be formulated to haveincreased firmness.

In yet another example of a silicone material that can be used, aproprietary UV-curing silicone gel (Momentive Performance Materials,Albany, N.Y. 12211). Part A and part B (catalyst) are mixed thoroughlywith the desired quantity of antimicrobial agent and the formulationcast onto a release liner contained by a curing “tool” (mold) and thetool placed onto a Dymax conveyer system with a Fusion UV systememploying an Iron D bulb. The silicone was readily cured following 2passes at a 2 ft/minute exposure rate.

The devices may be sterilized using gamma or electron beam radiation ispreferred for sterilizing such barrier dressings, as discussed in U.S.Pat. No. 5,454,886, the entirety of which is incorporated by referenceherein. The sterilized dressings should be sealed in packaging whichexcludes light penetration to avoid oxidation of any of theanti-microbial additives. Polyester, or metalized polymer and heatsealable pouches are preferred. The shelf life of anti-microbialdressings sealed in such a fashion is at least one year.

Referring to FIGS. 8-15 other embodiments of medical devices aredepicted. The medical devices may be single or multi-component medicaldevices and they may be utilized as dressings for transcutaneousdevices. Referring to FIG. 8, device 100 can include at least two layersof medical dressing materials laminated together by contact adhesion.Device 100 includes a two-layer silicone gel construct dressing inaccordance with the disclosure can include a first layer 102, which willbe skin facing in use, a second layer 104 which preferably forms anprotective layer. The layers 102 and 104 are shown to be laminatedtogether by contact adhesion onto one surface of 10. In accordance withthe disclosure, layer 102 can be considered composition 14 and layer 104can be considered substrate 12. Layer 104 can include an opening 106extending from a perimeter of layer 104 to a portion of layer 104. Thisopening can be configured in various shapes such as a circular openingto receive a transcutaneous device, for example.

Referring to FIGS. 9-11, medical device 120 is shown that includes abase 124 having an opening 106 configured to receive a transcutaneousmedical device. Base 124 can include composition 14 configured as atacky substance such as a tacky silicone gel and composition 14 can beassociated with one surface configured to engage a portion of epidermisof a patient. Device 120 can also include a cover 122 associated withbase 124 and configured to mate with another surface opposing the onesurface of base 124.

Cover 122 and base 124 can be associated via a common substrate 12 suchas fabric 126. As shown, cover 122 and base 124 can be situated 180degrees apart on opposite sides of the fabric 126. In accordance withexample configurations, In FIG. 2, cover and base can be mated byfolding pliable substrate 126 at hinge 125. As an example this canprovide an adhesion boundary between the cover and base and the commoncentral piece of fabric 126.

Referring to FIG. 10, cover 122 and base 124 are shown at 90° from eachother and intimating how the adhesion of cover 122 to substrate 126 canbe accomplished. Referring to FIG. 11 depicts device 120 securingtranscutaneous device 132 with the cover 122 adhering to substrate 126and securing device 132 through epidermal layer 22. Base 124 of device120 can further define a trough extending from the perimeter of the baseto the opening with the trough configured to receive at least a portionof the transcutaneous device. FIG. 12 details device 120 from a top downperspective detailing slit 106 and inner absorbent material 422, forexample.

Referring to FIG. 13 an embodiment of a medical device 320 is shownsecuring a subcutaneous glucose sensor 327 piercing the dermis 22 withits electronic connector 328 sitting external to body 20.

FIGS. 14 and 15 detail alternative cover/base device 222 as athree-layer device 220, to include a inner absorbent material 527surrounding tacky silicone barrier 224 and protective top layer material524.

In accordance with this disclosure, the cover and base may be may beformulated separately to include different additives. For example, thebase may include an antimicrobial agent and the cover may be free of anyadditive. In another embodiment, the base and cover can both beformulated to include an antimicrobial agent. In yet another embodiment,the base may include an organic-based antimicrobial agent and the covercan include an antimicrobial metal salt such as silver acetate thusalleviating contact of the skin by a silver salt containing polymer,which could lead to skin discoloration. The cover and base may be ofequivalent thicknesses or different thicknesses and may range fromapproximately 3 mm to approximately 15 mm, for example.

Also in accordance with this disclosure, the substrate may be a polymermaterial that includes polyurethanes, polyalkylenes, polysiloxanes, forexample in sheet or film or foam form or it may be a polymer material infabric form such as a woven, non-woven, or knitted fabric that includespolyesters, polyamides, and cellulosics that include natural fibers suchas cotton, wool or the like. Additionally, the substrate may be coatedwith the previous or other materials alone or in combination, suchpolyurethane, for example. Furthermore, the substrate may be designed towick fluid from the center of the device by controlling the thicknessand surface area of the material; for example, using a non-wovenmaterial such as a polyester. Substrate thicknesses may span a range ofapproximately 0.6 mm to approximately 5 mm, for example.

The medical devices as dressings can be sized to cover a significantportion of the device 132 that protrudes from the skin 22, and not justthe immediate skin area surrounding the penetration site. This may aidin limiting infection, since bacterial migration along the skin to thedevice 132 are minimized. A minimum dressing size will preferablyprovide at least 5 cm of protruding device 132 coverage, and morepreferably 15 cm coverage. Depending on the size of the transcutaneousmedical device, the termination point of the slit 106, may includeadditional cuts, preferably a cross-cut, or a penetrating hole (notshown), to allow the dressing barrier to fit around the device whilestill maintaining close contact with both the skin and protrudingsection of the medical device.

FIG. 12 shows device 420 from a top-down view with protective substrate124 and slit 106. Device 420 further includes absorbent material 422above a portion of substrate 124.

FIG. 13 demonstrates placement of device 320 over epidermis 22 ofpatient 20. Substrate 322 can be supported by composition 324, forexample, a protective layer over tacky silicone gel, with or without apharmaceutical agent. Device 320 can secure a biosensor with connector328 above substrate 322 and transcutaneous lead 327 below epidermis 22.Composition 324 can adhere to dermis 22 securing the biosensor in place.The biosensor can be an enzymatic sensor based upon glucose oxidase forexample. Generally, these glucose sensors evaluate glucose byelectrochemically measuring hydrogen peroxide resulting from theenzymatic digestion of glucose by glucose oxidase.

FIGS. 14 and 15 represent alternative embodiments of cover/base medicaldevice configurations. Referring first to FIG. 14, medical device 220can include base 224 with opening 106. Base 224 can be associated withcover 222 via a hinge portion 226, for example. Base 224 can include asubstrate 223 which may form part of hinge portion 226. FIG. 15represents another device embodiment, device 520, that can include base524 and cover 522 associated therewith. Base 524 can include substrate523 thereover, which may extend and attach to cover 522 via hinge 526.Above substrate can be absorbent material 527 which may also extend intoopening 106.

As described herein, the disclosure provides devices and methods for itsuse with a transcutaneous medical device, such as an intravascularcatheter, which punctures the skin of a patient and which has a portionof the medical device protruding from the skin or to dress a wound thatmay be surgically created or created by trauma. These transcutaneousdevices are prone to infection as a consequence of easy access ofbacteria to the open wound. As described, the devices of the presentdisclosure can be formed from a flexible, adherent silicone gel havingupper and lower surfaces, with the lower surface being the skin facingsurface in use and the top adherent surface protected by a substratesuch as a flexible woven, knitted, or non-woven fabric. The device mayhave an opening formed therein extending from one edge inwardly to atermination point within the confines of the device. Current dressingsfor protection against infection of transcutaneous devices generallyutilize a secondary transparent film (adhesive) dressing, such as withBIOPATCH®, in order to secure the device around the transcutaneousdevice. It has been recognized that these secondary dressings canirritate skin (allergic response) and damage epithelium when removedthus leading to further tissue irritation. The compositions of thedevices of the present disclosure can be more gentle to skin uponremoval and less likely to lead to an allergic response.

Specific embodiments of these devices may or may not include one or moreof a pharmaceutical agent or other functional agents such as a proteaseinhibitor incorporated into the silicone gel for placement adhered abovethe wound, without the use of additional adhesives at the upper andlower surfaces of the device. As an example use, the device can beplaced next to the skin, the opening allowing the base to surround thepuncture site and at least a portion of the transcutaneous deviceprotruding from the skin such that the lower surface of the base of thedevice is in contact with the skin while the upper surface of the baseof the device is also in contact with a portion of the transcutaneousdevice protruding from the skin. A cover may be utilized and joined tothe base and folded onto the top portion of the base such that the lowersurface of the cover is in contact with the upper surface of the baseand at least a portion of the transcutaneous device so as to secure thetranscutaneous device and provide another layer of antimicrobialprotection. In accordance with aspects of the disclosure, the portion ofthe transcutaneous device protruding from the skin can be exposed tocomposition 14 such as antimicrobial (silicone) material of the base.When affixing the cover to the base, a greater surface area of thetranscutaneous device may also be exposed to composition 14 as part ofthe silicone gel of the cover secures the transcutaneous device to thesubstrate of the base.

The embodiments herein describe devices and/or methods for preventinginfection, protein drug degradation, prolonging the use oftranscutaneous devices, and/or protecting wounds, including surgicalwounds from external or bacterial insult is disclosed. Embodiments ofthe disclosed medical device are conformal, and can include an adhesivesilicone barrier dressing surrounding a device that breaches the skin ofa patient undergoing diagnostic, drug, or nutritional therapy, orencompassing a surgically created wound or placing just prior to thecreation of a surgical wound. The conformal pressure sensitive barriermay be compounded to include one or more of a tissue preserving agent, adrug preserving agent, an antibiotic agent, an antibacterial agent, apain suppressing agent, or a tissue healing agent and/or the device maybe constructed to include an absorbent layer. Devices that may benefitfrom the conformal barrier device include, but are not limited to,biosensors, infusion devices, venous access devices, feeding tubes,wound drainage tubes, orthopedic pins, stomas, surgical drapes,catheters, and the like. Surgical wounds that may benefit from aconformal antimicrobial barrier device that has the ability to absorbsome wound exudate include those surgical incisions created in anyvariety of locations on the human body. The conformable barrier devicecan be flexible and adhesive thus allowing the device to followdifficult contours such as from the top of the foot onto the shin (90degree angle) or under the arm/armpit where a dressing may actually berequired to fold back on itself (180 degree angle). The soft-and-supplenature of the device can allow these kinds of wound cover to be worn incomfort and to act as a barrier to the ingress of pathogenicmicroorganisms.

Embodiments of the disclosure a device such as a dressing barrier devicethat can include a tacky silicone gel construct formulated with anactive pharmaceutical agent that has been finely divided and put througha sieve in order to ensure that the size of the particles is below acertain size. The device can be placed to overlie and surround an openwound supporting a transcutaneous device in order to minimize bacterialinfiltration, prevent tissue loss, and provide stability and protectionto active pharmaceutical agents susceptible to degradation resultingfrom inflammation. In addition, the device may be placed to overlie andsurround a (closed) surgical wound in order to minimize bacterialinfiltration, prevent external insult, provide a moist and antibacterialenvironment to the healing wound, and/or provide a healing aid (e.g.skin moisturizer) at the site of incision (staples or sutures).

In a another embodiment, composition 14 of the device can include theactive pharmaceutical agent, the silicone gel, and in the form of aconcentric part, a hydrocolloid or other water absorbing material inorder to aid with fluid absorption around the wound site. In anotherembodiment, the device includes both a base and cover; the cover can beextended to form two distinct tacky silicone gel constructs, one of thecover and one of the base, bound to opposite sides of substrate 12 suchas a protective layer and preferably with a non-overlapping boundarybetween the two constructs. In this arrangement, the base can be adheredto the skin surface surrounding the transcutaneous implant; thetranscutaneous device is surrounded by the base with the transcutaneousdevice resting perpendicular to an opening in the base. The cover canthen be folded onto the base to envelop the transcutaneous device andfix it in place while adhering to the upper protective layer of thebase. The upper protective layer can be a high surface area materialsuch as a woven polyester fabric, for example.

Embodiments of the disclosed devices have application to transcutaneousmedical devices such as those listed above, made from a wide variety ofmaterials, for example metals, including steel, titanium and aluminumand their alloys, latex, nylon, silicone, polyester, polyurethane, andother plastics and rubbers. Such transcutaneous devices are generallymade of bioinert or biocompatible materials. The transcutaneous devicemay take a variety of shapes including rod or tube shapes, hollow orsolid, and may be rigid or flexible, factors dictated by its intendedutility. One example transcutaneous device includes an infusion set usedwith an infusion pump as part of intensive drug therapy. The purpose ofan infusion set is to deliver a drug under the skin or into a centralvenous access point. It is a complete tubing system to connect aninfusion pump to the infusion system generally including a catheter,subcutaneous cannula, adhesive mount, quick-disconnect, and a pumpcartridge connector.

Devices of the disclosure may have application to surgically createdwounds that may be sutured closed or remain open with the devicecreating a barrier that surrounds the wound site and the devices of thedisclosure may, or may not provide an absorbent material that sits overthe open or closed wound. In addition, the absorbent material may beformulated to include an antimicrobial agent or any other number ofagents that may aid the healing of the wound.

Use of the devices of the disclosure as barrier dressings such as withtranscutaneous devices such as flexible catheters, for example, caninclude a release liner fitted onto the contact layer of the barrierdressing which is subsequently removed prior to the device being placedon the skin and around the transcutaneous device (e.g. catheter) bypassing or placing the catheter through the opening in the base contactlayer. In an alternative procedure, the barrier dressing is first placedaround the transcutaneous device and the release liner (which has beenslit in a separate operation) is removed one-half at a time. Prior toremoval of the release liner, the dressing can be rotated, oriented, andsituated, if needed, to ensure that the opening is roughly perpendicularto the long axis of the catheter, thus ensuring that the portion of thecatheter protruding from the skin is contacted by the upper surface ofthe base. Once the base is secure, the release liner of the cover isremoved and the cover folded over the base such that the lower surfaceof the cover is in contact with the portion of the catheter protrudingfrom the skin.

If the transcutaneous device is rigid, such as a temporary orthopedicpin, the base can be put in place as set out above, and the cover canthen be folded and secured around the portion of the pin protruding fromthe skin, in a tent-like manner or in another embodiment the cover isslit and each portion is placed independently in an overlapping fashion,since the pin generally protrudes at an angle normal to the skinsurface. One or more slits, holes, or openings may be provided in thecover in order to accommodate any type of transcutaneous device.Furthermore, the cover may be configured to include a secondary adhesivelayer, such as a clear adhesive medical tape such as a clear acrylic.The clear adhesive layer may be provided in place of the silicone gelcover or in addition to the silicone gel cover. The clear adhesive canbe affixed to the fabric layer and provided with a release liner forrapid placement over the transcutaneous device.

In vitro experiments involving embodiments of the present disclosure,formulated to include antimicrobial active pharmaceutical agentsmanufactured as described above and as described in greater detail inthe examples have been shown to control bacterial growth.

Examples of Formulations Formed into Barrier Dressing Configurations

Example 1

Nusil Med 6345 Formulated with Chlorhexidine Diacetate (CHXDA

-   10% CHXDA

13.995 g Part A, 13996 g Part B, 3.11 g CHXDA combined and stirred byhand to homogeneity.

The release profile for chlorhexidine is shown in the followinggraphical representation in FIG. 16.

Example 2

Nusil Med 6345 Formulated with Polyhexanide Hydrochloride (PHMB)

-   10% PHMB

14.04 g Part A, 14.02 g Part B, 3.12 g PHMB

The release profile for polyhexanide is shown in the following graphicalrepresentation in FIG. 17.

Example 3

Nusil Med 6345 Formulated with Octenidine Dihydrochloride

-   15% Oct.-   14.03 g Part A, 13.99 g Part B, 4.94 g octenidine

Example 4

Nusil Med 6345 Formulated with Silver Acetate

-   1% Ag acetate

13A7 g Part A, 16.47 g Part B, 3.04 g silver acetate

45:55 A:B

Example 5

Nusil Med 6345 Formulated with Polyvinylpyrrolidone (PVP) andPolyhexanide Hydrochloride (PHMB)

-   10% total solids (1:1 PHMB:PVP)

14.02 g Part A, 14.02 g Part B, 3.12 g PHMB/PVP

The release profile for polyhexanide is shown in the following graphicalrepresentation in FIG. 18.

Example 6

Nusil Med 6345 Formulated with Carboxymethylcellulose and ChlorhexidineDiacetate

-   15% CHX-DA

14.00 g part A, 14.02 g part B, 7.15 g CHX-DA, 1.75 g CMC

The release profile for polyhexanide is shown in the following graphicalrepresentation in FIG. 19.

Example 7

Nusil Med 6345 Formulated with Sodium Polystyrene Sulfonate(Crosslinked, Amberlite IRP69)

-   20% IRP69 (available from Rohman and Haas)-   13.2 g part A, 13.2 g part B, 6.6 g IRP69

Example 8

NusilMed 6345 Formulated with Silver Polystyrene Sulfonate (Crosslinked,Amberlite IRP69, Silver Modified)

-   20% IRP69-   13.2 g part A, 13.2 g part B, 6.6 g IRP69

In compliance with the statute, embodiments of the invention have beendescribed in language more or less specific as to structural andmethodical features. It is to be understood, however, that the entireinvention is not limited to the specific features and/or embodimentsshown and/or described, since the disclosed embodiments comprise formsof putting the invention into effect.

1. A composition comprising a tacky silicone material and at least one active pharmaceutical agent.
 2. The composition of claim 1 wherein the tacky silicone material is a gel.
 3. The composition of claim 1 wherein the pharmaceutical agent is one or more of an antibacterial agent, anti-inflammatory agent, nutrient, antibiotic agent, healing agent, antiproteolytic agent, anesthetic agent, oligodynamic agent, coagulation agent, anticoagulation agent, oligodynamic metal, moisturizing agent, and/or angiogenesis stimulating agent.
 4. The composition of claim 1 wherein the active pharmaceutical agent is an antimicrobial agent.
 5. The composition of claim 4 wherein the antimicrobial agent is one or more of chloroxylenol (parachlorometaxylenol), acedapsone; acetosulfone sodium; alamecin; alexidine; amdinocillin; amdinocillin; pivoxil; amicycline; amifloxacin; amifloxacinmesylate; amikacin; amikacin sulfate; aminosalicylic acid; aminosalicylate sodium; amoxicillin; amphomycin; ampicillin; ampicillin sodium; apalcillin sodium; apramycin; aspartocin; astromicin sulfate; avilamycin; avoparcin; azithromycin; azlocillin; azlocillin sodium; bacampicillin hydrochloride; bacitracin; bacitracin, methylenedisalicylate; bacitracin zinc; bambermycins; benzoylpas calcium; berythromycin; betamicin sulfate; biapenem; biniramycin; biphenamine hydrochloride; bispyrithionemagsulfex; butikacin; butirosin sulfate; capreomycin sulfate; carbadox; carbenicillin disodium; carbenicillin, indanyl sodium; carbenicillin phenyl sodium; carbenicillin potassium; carumonam sodium; cefaclor; cefadroxil; cefamandole; cefamandolenafate; cefamandole sodium; cefaparole; cefatrizine; cefazaflur sodium; cefazolin; cefazolin sodium; cefbuperazone; cefdinir; cefepime; cefepime hydrochloride; cefetecol; cefixime; cefmenoxime hydrochloride; cefmetazole; cefmetazole sodium; cefonicid monosodium; cefonicid sodium; cefoperazone sodium; ceforanide; cefotaxime sodium; cefotetan; cefotetan disodium; cefotiam hydrochloride; cefoxitin; cefoxitin sodium; cefpimizole; cefpimizole sodium; cefpiramide; cefpiramide sodium; cefpirome sulfate; cefpodoxime; proxetil; cefprozil; cefroxadine; cefsulodin sodium; ceftazidime; ceftibuten; ceftizoxime sodium; ceftriaxone sodium; cefuroxime; cefuroximeaxetil; cefuroximepivoxetil; cefuroxime sodium; cephacetrile sodium; cephalexin; cephalexin hydrochloride; cephaloglycin; cephaloridine; cephalothin sodium; cephapirin sodium; cephradine; cetocycline hydrochloride; cetophenicol; chloramphenicol; chloramphenicolpalmitate; chloramphenicolpantothenate complex; chloramphenicol sodium succinate; chlorhexidinephosphanilate; chlorhexidinediacetate, chlorhexidinedihydrochloride, chlorhexidinedigluconate, chlortetracycline bisulfate; chlortetracycline hydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin hydrochloride; cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin; clindamycin hydrochloride; clindamycinpalmitate hydrochloride; clindamycin phosphate; clofazimine; cloxacillinbenzathine; cloxacillin sodium; cloxyquin; colistimethate sodium; colistin sulfate; coumermycin; coumermycin sodium; cyclacillin; cycloserine; dalfopristin; dapsone; daptomycin; demeclocycline; demeclocycline hydrochloride; demecycline; denofungin; diaveridine; dicloxacillin; dicloxacillin sodium; dihydrostreptomycin sulfate; dipyrithione; dirithromycin; doxycycline; doxycycline calcium; doxycyclinefosfatex; doxycyclinehyclate; droxacin sodium; enoxacin; epicillin; epitetracycline hydrochloride; erythromycin; erythromycin acistrate; erythromycin estolate; erythromycin ethylsuccinate; erythromycin gluceptate; erythromycin lactobionate; erythromycin propionate; erythromycin stearate; ethambutol hydrochloride; ethionamide; fleroxacin; floxacillin; fludalanine; flumequine; fosfomycin; fosfomycintromethamine; fumoxicillin; furazolium chloride; furazoliumtartrate; fusidate sodium; fusidic acid; ganciclovir and ganciclovir sodium; gentamicin sulfate; gloximonam; gramicidin; haloprogin; hetacillin; hetacillin potassium; hexedine; ibafloxacin; imipenem; isoconazole; isepamicin; isoniazid; josamycin; kanamycin sulfate; kitasamycin; levofuraltadone; levopropylcillin potassium; lexithromycin; lincomycin; lincomycin hydrochloride; lomefloxacin; lomefloxacin hydrochloride; lomefloxacinmesylate; loracarbef; mafenide; meclocycline; meclocyclinesulfosalicylate; megalomicin potassium phosphate; mequidox; meropenem; methacycline; methacycline hydrochloride; methenamine; methenamine hippurate; methenamine mandelate; methicillin sodium; metioprim; metronidazole hydrochloride; metronidazole phosphate; mezlocillin; mezlocillin sodium; minocycline; minocycline hydrochloride; mirincamycin hydrochloride; monensin; monensinsodiumr; monovalent silver salts, nafcillin sodium; nalidixate sodium; nalidixic acid; natainycin; nebramycin; neomycin palmitate; neomycin sulfate; neomycin undecylenate; netilmicin sulfate; neutramycin; nifuiradene; nifuraldezone; nifuratel; nifuratrone; nifurdazil; nifurimide; nifiupirinol; nifurquinazol; nifurthiazole; nitrocycline; nitrofurantoin; nitromide; norfloxacin; novobiocin sodium; octenidinedihydrochloride, octenidinediacetate, octenidinedigluconate, ofloxacin; onnetoprim; oxacillin and oxacillin sodium; oximonam; oximonam sodium; oxolinic acid; oxytetracycline; oxytetracycline calcium; oxytetracycline hydrochloride; paldimycin; parachlorophenol; paulomycin; pefloxacin; pefloxacinmesylate; penamecillin; penicillins such as penicillin g benzathine, penicillin g potassium, penicillin g procaine, penicillin g sodium, penicillin v, penicillin v benzathine, penicillin v hydrabamine, and penicillin v potassium; pentizidone sodium; phenyl aminosalicylate; piperacillin sodium; pirbenicillin sodium; piridicillin sodium; pirlimycin hydrochloride; pivampicillin hydrochloride; pivampicillinpamoate; pivampicillinprobenate; polyhexamethylenebiguanide (polyhexanide hydrochloride, PI-IMB); polymyxin b sulfate; porfiromycin; propikacin; pyrazinamide; pyrithione zinc; quindecamine acetate; quinupristin; racephenicol; ramoplanin; ranimycin; relomycin; repromicin; rifabutin; rifametane; rifamexil; rifamide; rifampin; rifapentine; rifaximin; rolitetracycline; rolitetracycline nitrate; rosaramicin; rosaramicin butyrate; rosaramicin propionate; rosaramicin sodium phosphate; rosaramicinstearate; rosoxacin; roxarsone; roxithromycin; sancycline; sanfetrinem sodium; sarmoxicillin; sarpicillin; scopafungin; silver acetate; silver nitrate, nanocrystalline silver, silver polystyrene sulfonate (cross-linked” and non-cross-linked); silver carboxymethyl cellulose, silver polysaccharides (such as silver chondroitin sulfate and the like), silver carbene compounds, sisomicin; sisomicin sulfate; sparfloxacin; spectinomycin hydrochloride; spiramycin; stallimycin hydrochloride; steffimycin; streptomycin sulfate; streptonicozid; sulfabenz; sulfabenzamide; sulfacetamide; sulfacetamide sodium; sulfacytine; sulfadiazine; sulfadiazine sodium; sulfadiazine silver; sulfadoxine; sulfalene; sulfamerazine; sulfameter; sulfamethazine; sulfamethizole; sulfamethoxazole; sulfamonomethoxine; sulfamoxole; sulfanilate zinc; sulfanitran; sulfasalazine; sulfasomizole; sulfathiazole; sulfazamet; sulfisoxazole; sulfisoxazole acetyl; sulfisboxazolediolamine; sulfomyxin; sulopenem; sultamricillin; suncillin sodium; talampicillin hydrochloride; teicoplanin; temafloxacin hydrochloride; temocillin; tetracycline; tetracycline hydrochloride; tetracycline phosphate complex; tetroxoprim; thiamphenicol; thiphencillin potassium; ticarcillincresyl sodium; ticarcillin disodium; ticarcillin monosodium; ticlatone; tiodonium chloride; tobramycin; tobramycin sulfate; tosufloxacin; trimethoprim; trimethoprim sulfate; trisulfapyrimidines; troleandomycin; trospectomycin sulfate; tyrothricin; vancomycin; vancomycin hydrochloride; virginiamycin and/or zorbamycin.
 6. The composition of claim 1 wherein the active pharmaceutical agent is an anti-inflammatory agent.
 7. The composition of claim 6 wherein the anti-inflammatory agent is one or more of hydrocortisone, hydroxyltriamcinolone, alphamethyldexamethasone, dexamethasone-sodium phosphate, dexamethasone; beclomethasone dipropionate, clobetasolvalerate, desonide, des oxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolonevalerate, fluadrenolone, fluclaroloneacetonide, fludrocortisone, flumethasonepivalate, fluosinoloneacetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinoloneacetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosonediacetate, fluradrenaloneacetonide, medrysone, amc, amcinafide, betamethasone and the balance of its esters, chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasonedipropionate, betamethasonedipropionate, triamcinolone prostaglandin H synthetase inhibitors (Cox I or Cox II), flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam, sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456, tenoxicam, carprofen, cyclooxygenase type II selective inhibitors, vioxx, celecoxib, P54, etodolac, L-804600, S-33516; PAF antagonists, A-137491, ABT-299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant, modipafant, PDE IV inhibitors, ariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline, CG-1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004, and/or roflumilast.
 8. The composition of claim 1 wherein the active pharmaceutical agent is an antiproteolytic agent.
 9. The composition of claim 8 wherein of the antiproteolytic agent is one or more of amprenavir (Agenerase), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), ritonavir (Norvir), saquinavir (Fortovase), and nelfinavir (Viracept), salts of ethylene diamine tetracetic acid, salts of polystyrene sulfonate, and sulfated oligo & polysaccharides. 10-57. (canceled) 